Background: Alpha lipoic acid (LA) is a natural product that is a potent antioxidant. It has an excellent safety profile and has been used in Europe for over 2 decades for the treatment of diabetic peripheral neuropathy. Studies of prolonged LA infusions in insulin resistant type 2 diabetics (T2D) have indicated that LA markedly improves insulin action. However, studies of orally administered LA in T2D have not shown major effects on this function. It is hypothesized that the short plasma half of LA and its rapid elimination limits its use as an oral agent for insulin resistance. Recently controlled release LA has become available, and appears to improve diabetic control in T2D patients. We propose, therefore, to study LA's effects on insulin-stimulated glucose uptake in a well characterized population of insulin resistant subjects. These subjects are non- obese, non diabetic subjects with insulin resistance. This population is ideal for an analysis of the effects of LA on insulin action, because they are as insulin resistant as T2D patients but do not have the important confounders of hyperglycemia and obesity. Because these insulin resistant subjects are at risk for the development of T2D, the Metabolic Syndrome, and coronary artery disease (CAD), a demonstration of the beneficial effects of LA on insulin action could ultimately have important public health consequences. Hypotheses: 1) LA will improve insulin sensitivity in a general population of non-obese, insulin-resistant, non-diabetic subjects; and 2) The improvement of insulin action by LA is due to its effects on the major components of the insulin signaling pathway (insulin receptor, IRS proteins, PI 3-kinase, PKB/AKT and GLUT4); and/or regulators of the insulin signaling pathway (PTP 1B, PC-1, IKK, NF-kB and PKC). Methods: The insulin sensitivity of 180 subjects will be initially estimated by insulin sensitivity index. The most insulin resistant subjects will then be randomized to 6 weeks of therapy with either LA or placebo. Several markers of oxidative stress will be measured. To quantitate LA-induced improvements in both in insulin sensitivity and the insulin signaling pathway, euglycemic hyperinsulinemic clamps with muscle biopsies will be performed before and after treament. [unreadable] Anticipated Results and Significance: We believe these studies will (1) confirm the beneficial effect of LA on insulin sensitivity; (2) further our understanding of the molecular mechanisms of LA action; and (3) form a basis for a larger project examining the long term efficacy of LA in preventing the development of T2D and CAD. [unreadable] [unreadable] [unreadable]